Osteostimulating elastomeric bone filling compositions

ABSTRACT

A bone filling composition includes a bone filler. The bone filler includes microparticles of at least one elastomeric material. The at least one elastomeric material includes a poly(glycerol sebacate)-based thermoset. The poly(glycerol sebacate)-based thermoset may be porous thermoset poly(glycerol sebacate) flour, thermoset poly(glycerol sebacate) microspheres, or a combination thereof. In some embodiments, the bone filling composition is a bone filling composite that further includes a carrier material including a poly(glycerol sebacate) resin. A method of forming a bone filling composite includes selecting a bone filler and mixing the bone filler with a carrier material to form the bone filling composite. A method of treating a bony defect includes molding a bone filling composite and placing the bone filling composite in the bony defect. The bone filling composite includes a bone filler mixed with a carrier material.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 16/263,064 filed Jan. 31, 2019, which claims priority to andthe benefit of U.S. Provisional Application No. 62/624,579 filed Jan.31, 2018 and U.S. Provisional Application No. 62/720,296 filed Aug. 21,2018, all of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present application is generally directed to bone fillingcompositions. More specifically, the present application is directed toosteostimulating elastomeric bone filling compositions.

BACKGROUND OF THE INVENTION

The current state-of-the-art in bone filler devices is to usehydroxyapatite (HA; Ca₁₀(PO₄)₆(OH)₂) or other salts of calcium andphosphate as an osteoconductive material. The idea behind the use of thecalcium salts is that they represent the mineral composition of hardbone in composition and physical properties. However, bone is composedof both hard osseous (cortical) tissue and softer osseous (cancellous)tissue, and during the healing process, bone first goes through a softelastomeric (osteoid) phase prior to mineralization.

These changes in physical properties during the healing process providemechano-biologic cues to the local cellular environment, promoting theexpression of the appropriate cell types required at that phase of thehealing process. The presence of such hard mineral biomaterials causesthe expression of cell types for late-stage healing, thereby skippingthe earlier osteoid period of healing. Current approaches to bonehealing, using hard, brittle salts of calcium and phosphate to stimulatebone growth through simulation of the mechanical properties of maturecortical bone, disregard the tissue properties during the early phasesof bone regeneration.

Commercial fillers are used in long bone defects and dentalapplications. These fillers contain a salt and may additionally includea carrier material, which may be a synthetic material or a biologicmaterial, such as, for example, collagen. In some cases, plasticmaterials are included in the commercial filler. These plasticmaterials, however, do not transmit stress but instead shield adjacentmaterials from stress. The carrier only acts as a binding matrix to keepthe calcium salt within the bone defect. It does not provide anytherapeutic effect. If the filler contains only a salt, the filler istypically mixed with blood and placed within the defect.

The problems associated with conventional putty formulations include,but are not limited to, their inclusion of animal-based carriermaterials, their inability to be molded to fit the defect geometry,their inability to remain in the defect site, their resistance toirrigation, their lack of antimicrobial properties, and the need for atwo-step process of mixing salt with blood to achieve an appropriateconsistency.

What is needed is an elastomeric bone filling composition that promotesthe expression of the appropriate cell types during the early phases ofbone regeneration.

BRIEF DESCRIPTION OF THE INVENTION

In an embodiment, a bone filling composition includes a bone filler. Thebone filler includes microparticles of at least one elastomeric materialand a filler dopant in the elastomeric material. The at least oneelastomeric material includes a poly(glycerol sebacate)-based thermoset.

In another embodiment, a method of forming a bone filling compositeincludes selecting a bone filler. The method also includes mixing thebone filler with a carrier material to form the bone filling composite.The bone filler includes microparticles of at least one elastomericmaterial. The at least one elastomeric material includes a poly(glycerolsebacate)-based thermoset.

In yet another embodiment, a method of treating a bony defect includesmolding a bone filling composite and placing the bone filling compositein the bony defect. The bone filling composite includes a bone fillermixed with a carrier material. The bone filler includes microparticlesof at least one elastomeric material. The carrier material includes apoly(glycerol sebacate) resin.

Various features and advantages of the present invention will beapparent from the following more detailed description, taken inconjunction with the accompanying drawings which illustrate, by way ofexample, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an image of thermoset PGS microspheres in an embodiment of thepresent disclosure.

FIG. 2 shows a method of treatment using a bone filling composition ofthe present disclosure.

FIG. 3 shows the zero-shear viscosity profiles of MgO-doped PGS resinsin embodiments of the present disclosure.

FIG. 4 shows the resin crystallization temperatures for PGS and forMgO-doped PGS resins in embodiments of the present disclosure.

FIG. 5 shows the toughness values measured by tensile testing forcontrol PGS and MgO-doped PGS of the present disclosure.

FIG. 6 shows FTIR spectra of thermoset PGS and thermoset MgO-doped PGSof the present disclosure.

Wherever possible, the same reference numbers will be used throughoutthe drawings to represent the same parts.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The use of a soft, elastomeric material promotes the natural bonehealing cascade by first initiating the osteoid phase of bone healing.The elastomeric material transmits stress, which promotes the bonehealing process.

In exemplary embodiments, bone growth is stimulated through the use of abone filler through mechanisms that better reproduce themechano-biologic response of the early phases of bone healing. The bonefiller includes microparticles of at least one elastomeric material. Themicroparticles may include porous, elastomeric bone filling materialand/or elastomeric microspheres.

In exemplary embodiments, the bone filler is part of a bone fillingcomposition. In some embodiments, the bone filling composition is a bonefilling composite. The bone filling composite includes a bone filler, anoptional carrier material, and one or more optional carrier dopants. Thebone filling composite is conformable and moldable, has a stronginteraction/adhesion with tissue, and/or is ready-to-use out of the box.

In exemplary embodiments, the elastomeric material includes apoly(glycerol sebacate) (PGS)-based thermoset based on a PGS-basedresin. In some embodiments, the PGS-based resin is a PGS resin. Inexemplary embodiments, the PGS resin may be formed in a water-mediatedreaction, such as described in U.S. Pat. No. 9,359,472, which is herebyincorporated by reference in its entirety, in the presence or in theabsence of a doping mineral. The PGS resin may also be mixed with aporogen prior to curing and thermosetting. The PGS resin and porogen maybe mixed at a weight-to-weight (w/w) ratio in the range of 1:1 to 1:3,alternatively 2:3 to 2:5, alternatively about 1:2, or any value, range,or sub-range therebetween. The porogen may then be removed by dissolvingin an appropriate solvent to form microparticles of a porous thermosetPGS flour or porous thermoset PGS microspheres.

In exemplary embodiments, the microparticles of the bone filler includea porous thermoset PGS-based flour. In some embodiments, the porousthermoset PGS-based flour is a porous thermoset PGS flour. After formingthe PGS resin and optionally mixing the PGS resin with a doping mineraland/or a porogen, the PGS resin may be cured and then ground to form theporous thermoset PGS flour. The porous thermoset PGS flour has anirregular surface contour and geometry. The curing and grinding to formthe flour may be as described in U.S. Patent Application Publication No.2017/0246316, which is hereby incorporated by reference in its entirety.

In other exemplary embodiments, the microparticles of the bone fillerinclude thermoset PGS-based microspheres. The thermoset PGS-basedmicrospheres may be porous or non-porous. In some embodiments, thethermoset PGS-based microspheres are thermoset PGS microspheres. FIG. 1is an image of thermoset PGS microspheres without pores. After formingthe PGS resin and optionally mixing the PGS resin with a doping mineraland/or a porogen, the PGS resin may be cured to form the thermoset PGSmicrospheres. The PGS microspheres have a spherical geometry and asmooth surface contour. In exemplary embodiments, the thermoset PGSmicrospheres are formed without a mold by a method described in U.S.Patent Application Publication No. 2018/0280912, which is herebyincorporated by reference in its entirety.

In other exemplary embodiments, the microparticles of the bone fillerinclude a mixture of porous thermoset PGS flour particles and thermosetPGS microspheres. The PGS flour particles have a highly irregulargeometry in contrast to the highly regular geometry of the PGSmicrospheres. In exemplary embodiments, the relative amounts of PGSflour particles and PGS microspheres in the bone filler may be selectedto provide a bone filling composition having a specific morphology for aspecific application of the bone filling composition.

In other embodiments, the filler material includes another PGS-basedthermoset material, such as, for example poly(glycerol sebacateurethane) (PGSU), poly(glycerol sebacate acrylate) (PGSA), or a PGSadduct with pendant groups, such as, for example, lysine (PGS-lysine) orsalicylic acid (PGS-salicylic acid).

In exemplary embodiments, the porous thermoset PGS-based flour is formedfrom a PGS-based resin, a porogen, and an optional filler dopant. Inexemplary embodiments, the thermoset PGS-based microspheres are formedfrom a PGS-based resin, a porogen, and an optional filler dopant.

Appropriate porogens may include an inorganic salt, bioglass, a sugar,or polymeric beads. Appropriate porogen inorganic salts may include, butare not limited to, sodium chloride (NaCl), potassium chloride (KCl),monocalcium phosphate (Ca(H₂PO₄)₂), dicalcium phosphate (CaHPO₄),tricalcium phosphate (TCP; Ca₃(PO₄)₂), monopotassium phosphate (KH₂PO₄),dipotassium phosphate (K₂HPO₄), tripotassium phosphate (K₃PO₄), orcombinations thereof.

Suitable filler dopant materials may include, but are not limited to, amineral, magnesium oxide (MgO), calcium oxide (CaO), dispersedhydroxyapatite, TCP, silicon dioxide (SiO₂), titanium dioxide (TiO₂),bioglass, magnesium chloride (MgCl₂), monomagnesium phosphate(Mg(H₂PO₄)₂), dimagnesium phosphate (MgHPO₄), magnesium phosphatetribasic (Mg₃(PO₄)₂), magnesium sulfate (MgSO₄), calcium chloride(CaCl₂)), monocalcium phosphate, dicalcium phosphate, tricalciumphosphate, calcium sulfate (CaSO₄), or combinations thereof.

In exemplary embodiments, the porous thermoset PGS flour is formed froma PGS resin having a weight average molecular weight in the range of 10kilodaltons (kDa) to 20 kDa mixed with a porogen and cured for 24 to 96hours, depending on the porogen concentration and the desired propertiesof the resultant flour. The cured mixture is then ground, and the groundmixture is exposed to a solvent that dissolves and removes the porogenwhile leaving the porous thermoset PGS flour. While any appropriatesolvent may be used, the solvent is typically water or an aqueoussolution. The resulting porous thermoset PGS flour may be used as bonefiller.

As the resulting pore size is directly related to the particle size ofthe porogen, the size of the porogen may be selected based on thedesired pore size, which may be based on the expected size of the flourparticles. An appropriate size ratio of the average flour particle sizeto the average porogen particle size may be in the range of about 4:1 toabout 10:1, alternatively in the range of about 5:1 to about 8:1, or anyvalue, range, or sub-range therebetween. In some embodiments, theaverage particle size of the porogen is in the range of about 25micrometers (μm) or less, alternatively about 25 μm to about 200 μm,alternatively about 25 μm to about 50 μm, alternatively about 50 μm toabout 100 μm, or any value, range, or sub-range therebetween. Thethermoset is then ground into a rough to fine flour with an averageparticle size of about 100 μm or less, alternatively 100 μm to 800 μm,alternatively 100 μm to 200 μm, alternatively 200 μm to 500 μm, or anyvalue, range, or sub-range therebetween.

The thermoset PGS may be ground by any appropriate grinding process,including, but not limited to, cryomilling, disc milling, hammermilling, or ball milling, to form the PGS flour.

The molecular weight and/or the glycerol:sebacate stoichiometry of thePGS may be selected to provide a thermoset PGS flour with certaindesired or predetermined properties. Alternatively or additionally, thePGS may be modified by the inclusion of MgO, bioglass, and/or acid.

In some embodiments, the composition of the PGS microspheres includes aPGS resin having a weight average molecular weight in the range of fromabout 5,000 to about 50,000 Da. In some such embodiments, the resin hasa weight average molecular weight in the range of from about 10,000 toabout 25,000 Da.

Different methods of microparticle forming technology, which mayinclude, but are not limited to, emulsions, phase-separation, spraydrying/congealing, spinning disk atomization, wax coating and hot melt,and freeze drying, may be utilized to form PGS microparticles orcore-shell PGS microparticles prior to curing in a continuous matrixphase.

Depending on the materials and conditions, particles having a range ofphysical and chemical properties may be obtained. In some embodiments,the particles are microspheres having an average size in the range of 1μm to 1 mm. In some embodiments, the microspheres have a particle sizein the range of 50 μm to 300 μm, alternatively in the range of 100 μm to500 μm, or any value, range, or sub-range therebetween.

Exemplary embodiments can provide for microspheres of PGS or otherbiodegradable polymers to be created and cured into an elastomer in onecontinuous step, allowing for the formation of microspheres that retaintheir spherical shape during thermal curing at elevated temperaturesand/or microwave curing.

In some embodiments, concepts of microparticle formation and thermalcuring of PGS are utilized and combined into a single step to formcrosslinked PGS microspheres. In an exemplary embodiment, the process ofmaking PGS microspheres occurs in a single vessel.

In some embodiments, neat PGS microspheres are manufactured by providinga liquid that is phase-incompatible with PGS. The phase-incompatibleliquid may be any liquid or viscous medium that is phase-incompatiblewith the PGS. In some embodiments, the phase-incompatible liquid isnon-reactive with the PGS, such as, for example, a mineral oil or amixture of higher alkanes and/or cycloalkanes.

In some embodiments, methods take advantage of specific gravity andbuoyancy in a vertical column. A phase-incompatible liquid of higherspecific gravity than PGS fills a vertical column. A hypodermic needleinserted into the liquid at the bottom of the column permitsintroduction of the PGS resin from a reservoir. The vertical column andreservoir may be heated to allow flow. The vertical column may besurrounded with an appropriate radiation source, such as, for example,infrared (IR) or microwave, that is configured to deliver energy throughthe vertical column, the phase-incompatible liquid, and the PGS resin,to cure the PGS resin to a thermoset PGS microsphere.

The porous thermoset PGS flour and/or the thermoset PGS microspheres maybe dusted or impregnated with salts of calcium and phosphate to provideadditional osteoconductive cues while maintaining the elastomericproperties of the flour. Dusting may include tumbling or otherwisemixing the flour and/or microspheres in the salt to coat the flourand/or microsphere particles with the powder. Impregnation may includecompressing the dusted or otherwise coated flour and/or microspheres toembed the powder in the particles.

The bone filler may contain demineralized bone matrix (DBM), bone chips,or other autologous materials that have been shown to be osteoinductive.

The bone filler may contain bone morphogenic proteins (BMPs) or otherbiologics that have been shown to enhance bone regeneration.

The PGS flour and/or PGS microspheres may be mixed with blood, serum, oranother biologic medium prior to implantation. Alternatively, the PGSflour and/or PGS microspheres may be added directly to a bony void.

In exemplary embodiments, a bone filler formulated as described above iscombined with a carrier material including a PGS resin to provide a bonefilling composite as an out-of-the-box, moldable putty to be used tofill bony defects. PGS resin is a non-animal-based, non-inflammatory,resorbable binder for the bone filler. The PGS resin degrades fasterthan the PGS flour and/or PGS microspheres due to a lower crosslinkingdensity of the PGS resin. As the resin degrades, any pores present inthe flour and/or microspheres emerge and provide guidance cues forosteoblast infiltration. The elastomeric properties of the flour and/ormicrospheres simulate the mechanical forces of early bone growth,thereby promoting early collagen deposition.

Appropriate carrier materials may include, but are not limited to, PGSresin; a polypeptide, such as, for example, collagen; a polysaccharide,such as, for example, alginate; or a glycosaminoglycan, such as, forexample, hyaluronic acid; a hydrogel; or combinations thereof. In someembodiments, the carrier material has antimicrobial properties. In someembodiments, the carrier material is a PGS resin. In some embodiments,the PGS resin carrier material is functionalized with other fatty acidsor glycerol esters having antimicrobial properties, such as, forexample, monolaurate.

The porous thermoset PGS flour and/or thermoset PGS microspheres may bemixed with a PGS resin composition to form a bone filling composite. ThePGS resin composition includes a hot PGS resin and may include one ormore carrier dopants. Carrier dopants may include, but are not limitedto, glycerol, bioglass, one or more salts, or combinations thereof.Suitable carrier dopant materials may include, but are not limited to, amineral, magnesium oxide, calcium oxide, dispersed hydroxyapatite, TCP,silicon dioxide, titanium dioxide, bioglass, magnesium chloride,monomagnesium phosphate, dimagnesium phosphate, magnesium phosphatetribasic, magnesium sulfate, calcium chloride, monocalcium phosphate,dicalcium phosphate, tricalcium phosphate, calcium sulfate, silver ions,a silver salt, or combinations thereof.

The elastomeric material and carrier dopant may be at a w/w ratio in therange of 1:1 to 1:3, alternatively 2:3 to 2:5, alternatively 2:3 to 1:2,alternatively 1:2 to 2:5, alternatively about 1:2, or any value, range,or sub-range therebetween. The elastomeric material and glycerol may beat a w/w ratio in the range of 10:1 to 2:1, alternatively 8:1 to 3:1,alternatively 5:1 to 3:1, alternatively 5:1 to 4:1, alternatively 4:1 to3:1, alternatively about 5:1, alternatively about 4:1, alternativelyabout 3:1, or any value, range, or sub-range therebetween. Theelastomeric material and hot PGS resin may be at a w/w ratio in therange of 2:1 to 1:2, alternatively 3:2 to 2:3, alternatively about 1:1,or any value, range, or sub-range therebetween. The hot PGS resin ispreferably at a temperature of at least 90° C., such as, for example,90° C. to 120° C. The carrier dopant may, for example, be a salt ofcalcium and phosphate, such as, for example, hydroxyapatite or TCP. Insome embodiments, the porosity of the microparticles is selected basedon trabecular bone properties. In some embodiments, the porosity of theporous thermoset PGS flour is in the range of 50% to 90%.

The PGS resin of the filler or the carrier may be synthesized to containMgO, hydroxyapatite, TCP, bioglass, or another inorganic salt to mimicnative bone. These inorganic additives may be part of the bone filler orresin carrier, where incorporation into the resin results in an earlyrelease to potentially accelerate healing.

Resin and/or flour particles and/or microsphere particles may besynthesized from monomers containing reactive moieties, such as, forexample, acrylates, methacrylates, isocyanates, and/or sulfur, whichallow the filler or carrier to cure in situ via heat, ultraviolet (UV)radiation, or another energy source.

In exemplary embodiments, the bone filling composite is molded to ashape of a bony defect and placed in the bony defect. The molding mayoccur before, during, and/or after placing the composite in the bonydefect.

In exemplary embodiments, porous elastomeric particles placed in a bonydefect provide the mechanobiologic cues of early-stage bone healing. Theelastomeric particles stimulate bone growth, whereas conventionaltreatments use materials that are diametrically opposite to theelastomeric particles in physical properties.

A bone filling composite may be formulated into a sheet to act as a bonewrap. Such sheets may be used to augment bone plates or metal framingstructures to encourage bone growth and incorporation of the metalstructures.

Many current calcium and phosphate-containing particulates arefabricated using biologic scaffolds, such as, for example, algae, toform intricate 3D porous structures. PGS resin may also be used to fillsimilar templates to create novel 3D structures post-cure andpost-template removal. Microfluidics may be used to fill micron-scalemolds.

In some embodiments, compositions of the present disclosure are used inthree-dimensional (3D) printing ink to form 3D articles forimplantation.

MgO-doping provides an additional way to modify the physical propertiesof PGS thermosets, as the inclusion of MgO acts to increase the modulus,tensile strength, and elongation, as shown in the Examples. Withoutwishing to be bound by theory, the mechanism for this action may be dueto direct coupling of the PGS polymer to the hydroxylated MgOHparticles, increased hydrogen bonding, or through ionomer formationbetween the Mg²⁺ and carboxylic acid groups present in the PGS.

In one application, the bone filling composition may aid in healing andrecovery from femoral head deformity following ischemic necrosis, afairly common deformation of children's hip joints. In cases of vasculardisruption to the femoral head, the disruption of the blood supply tothe femoral head may lead to bone, marrow, and cartilage necrosis andcessation of endochondral ossification in the femoral head. This weakensthe femoral head such that it is no longer able to maintain its shapeunder the normal mechanical loadings on the femoral head. The resultingtrabecular compression and deformation of the femur head leads to a hipjoint displacement. Conventional recovery may include bedrest for up toa year to minimize the mechanical load while the femoral head heals.

Referring to FIG. 2, after trabecular compression and deformation of thefemur head, a cannula 20 is used to inject a bone filling compositionincluding microparticles 22 into the necrotic trabecular space 24 of thefemur head 26. The bone filling composition can be used to fill,inflate, maintain, and reform the void space. The microparticles 22 aidin re-scaffolding and remodeling the necrotic void, and the elastomericnature of the microparticles 22 allows for rebuilding andre-ossification of the resorbed areas and restoration of the shape ofthe femur head 26. The microparticles 22 may be doped (e.g. with MgO) orundoped and may include porous thermoset PGS flour, thermoset PGSmicrospheres, or a combination of flour and microspheres. In someembodiments, microspheres are preferred, as the form of themicroparticles 22 may be more amenable to injection through a cannula 20into the necrotic trabecular space 24.

EXAMPLES

The invention is further described in the context of the followingexamples which are presented by way of illustration, not of limitation.

Example 1

A porous thermoset PGS flour was produced by first adding about 15 grams(g) of hot (≥90° C.) PGS resin to about 30 g of sieved, crystalline NaClsalt having an average particle size about 106 μm or less. The materialswere mixed by a mixer (FlackTek, Inc., Landrum, S.C.) at 2000revolutions per minute (rpm) for about 2 minutes. The resultant pastewas placed into a round aluminum dish and smoothed to a film about 2millimeters (mm) thick. The film was thermoset at a temperature of about120° C. and a pressure of about 10 Torr for about 24 hours. Theresultant solid film was removed from the aluminum dish in crumbledpieces and placed into a jar and then mixed by the FlackTek mixer at2000 rpm for about 1 minute to break/grind the flour to smaller particlesizes.

About 50 mL of deionized water (diH₂O) was added to the jar and the jarwas sonicated for about 5 minutes to dissolve away the NaCl salt. Thesolvent was decanted, and the dissolve step was repeated three times.The resultant flour was then transferred to a Buchner funnel with filterpaper in place. The PGS flour was placed in the Buchner funnel andrinsed by vacuum filtration with 1000 mL of diH₂O. The resultant flourwas dried in a vacuum desiccator at a pressure of about 10 Torr forabout 18 hours. The PGS flour particles were imaged for size andporosity by scanning electron microscopy (SEM).

Example 2

A PGS bone filling composite was produced by adding about 2.5 g of theporous thermoset PGS flour from Example 1 to about 4.4 g of TCPparticles having a particle size in the range of about 50-150 μm andabout 0.6 g of glycerol. The materials were mixed by a FlackTek mixer atabout 2000 rpm for about 30 seconds, followed by a dwell time of about20 minutes. To this mixture, about 2.5 g of hot (≥90° C.) PGS resin wasadded as a carrier and mixed at about 2000 rpm for about 1 minute. Theresultant bone filling composite was soft and moldable. The bone fillingcomposite was characterized by manual manipulation and by SEM/energydispersive X-ray spectroscopy (EDS) for organic/mineral homogeneity.

Example 3

An MgO-doped PGS resin was formed in a water-mediated reaction based ona method described in U.S. Pat. No. 9,359,472, which is herebyincorporated by reference in its entirety, where the MgO particles wereintroduced before the 24-hour distillation step. The MgO was provided inan amount of about a 1:200 weight ratio with respect to the PGS resin.Glycerol was added to a reaction vessel with water under stirring. Afterdissolution of the glycerol, sebacic acid was added to the reactionvessel. The amounts of glycerol and sebacic acid were selected toprovide about a 3:2 molar ratio of free hydroxyl groups to free carboxylgroups. The reaction vessel was then fitted with a condenser to refluxwater during the melt and stir steps of the polymerization, with thecondenser temperature being set to 2.5° C. The reaction vessel was thenheated to a temperature of 160° C. under stirring for approximately 70minutes.

After the sebacic acid melted, the temperature was set to 150° C. andthe mixture was stirred under reflux for 90 minutes.

The condenser was then removed, the MgO particles were added, and thereaction vessel was fitted with a distillation condenser to remove waterfrom the reaction vessel. A nitrogen purge was applied to the reactionvessel and the temperature was set to 120° C. During the distillation,the contents of the reaction vessel were stirred at 120° C. for 24hours.

Next, a vacuum line was connected to the distillation condenser and thesub-atmospheric pressure was applied to the contents of the reactionvessel. The pressure was reduced slowly and stepwise over about 120minutes to approximately 20 Torr.

Once the pressure in the reaction vessel reached about 20 Torr, thevacuum pump was set to 10 Torr. Following the application of vacuum atabout 10 Torr, the reaction vessel was left to react for 26 hours at130° C. under stirring, with the sub-atmospheric pressure set to 10Torr.

Example 4

In a parallel synthesis method to that of Example 3, an MgO-doped PGSresin was formed, where the MgO particles were introduced after the24-hour distillation step rather than before the 24-hour distillationstep as described in Example 3.

Example 5

A porous MgO-doped (about 0.5% w/w) PGS flour was prepared as in Example1, except that unsieved NaCl salt was used in place of sieved NaCl salt,the MgO-doped PGS resin of Example 3 was used in place of neat PGSresin, and about a 1.5:1 w/w ratio of NaCl salt to MgO-doped PGS resinwas used. The porous MgO-doped PGS flour was characterized by SEM/EDSfor organic/mineral homogeneity, with the results being similar to thoseof Example 1.

Example 6

A porous MgO-doped PGS bone filling composite was produced by addingabout 5.9 g of porous MgO-doped PGS flour from Example 3, to about 1.0 gof TCP particles having a particle size in the range of about 50-150 μmand about 0.6 g of glycerol. The materials were mixed in a FlackTekmixer at about 2000 rpm for about 30 seconds, followed by a dwell timeof about 2 hours. To this mixture, about 2.5 g of hot (≥90° C.)MgO-doped PGS resin of Example 3 was added as a carrier and mixed atabout 2000 rpm for about 1 minute. The resultant bone filling compositewas soft and moldable. The porous MgO-doped PGS bone filling compositewas characterized by SEM/EDS for organic/mineral homogeneity, with theresults being similar to those of Example 2.

Example 7

Post-synthesis, the MgO-doped PGS resins of Example 3 and Example 4 wereevaluated using differential scanning calorimetry (DSC) and wereanalyzed rheologically to assess the resins' thermal and rheologicalproperties, respectively. The MgO-doped PGS resins of Example 3 andExample 4 were analyzed to evaluate the effect of hydroxylating the MgOand incorporating it into PGS.

A portion of each resin was loaded into an aluminum pan, targeting afilm thickness of about 2 mm, and thermoset at about 120° C. for about73.5 hours. As a control, three pans of stock PGS resin, produced by asimilar synthesis method but not doped with MgO, were also thermosetwith the same specifications alongside the MgO-doped PGS resin toprovide control data for all thermoset properties. The resins and theirrespective thermosets were tested under DSC and tensile analyses toassess their thermal and mechanical properties. Tensile testing wasperformed according to ASTM D6381. Samples were also cut from each pieceof thermoset material and crosslink density measurements were takenaccording to a method outlined in U.S. Pat. No. 8,043,699, which ishereby incorporated by reference in its entirety.

As observed in the reaction vessels, the MgO-doped PGS resin of Example3 was slightly cloudy with no dispersed particulate, while the MgO-dopedPGS resin of Example 4 had visible suspended particulate matter. FIG. 3shows the control resin zero-shear viscosity profile, the Example 3resin zero-shear viscosity profile, and the Example 4 resin zero-shearviscosity profile. These viscosity measurements, taken duringrheological analysis, indicate that both MgO-doped PGS resins hadsubstantially higher viscosities compared to typical PGS (about 9 Pa·sas compared to about 3 Pa·s, respectively), although the particulate inthe resin from Example 4 caused the zero-shear viscosity profile toappear erratic.

DSC measurements of both the resinous and thermoset forms of the Example3 MgO-doped PGS resin and thermoset, the Example 4 MgO-doped PGS resinand thermoset, and the control PGS resin and thermoset indicated thatthe MgO-doped PGS samples exhibited lower crystallization temperaturesas compared to the PGS control samples. FIG. 4 shows the Example 3resinous form crystallization temperature, the Example 4 resinous formcrystallization temperature, and the undoped PGS control resinous formcrystallization temperature. The depressed crystallization temperaturesof the MgO-doped PGS samples, relative to the PGS control samples, mayindicate a more reacted and/or crosslinked polymer, as that is the trendwith undoped PGS. Other chemical interactions between the MgO and thePGS may also or alternatively influence the crystallization behavior ofthe material.

FIG. 5 shows the toughness values for the undoped PGS controlthermosets, the Example 3 MgO-doped PGS thermosets, and the Example 4MgO-doped PGS thermosets subjected to tensile testing. Overall, theMgO-doping yielded a tougher thermoset material as compared to thecontrol PGS. The MgO-doped PGS thermoset of Example 3 had a highertoughness than that of the MgO-doped PGS thermoset of Example 4. Withoutwishing to be bound by theory, this can be explained in one of two ways:first, the process of Example 3 allowed the MgO material a greaterchance to react with the PGS, as the MgO was added earlier in thepolymerization process, more hydroxylation of the MgO from watercontained in the reactor vessel, and/or better homogeneity in the finalproduct as compared to the Example 4 process. Second, thelarger/non-uniform size of the embedded MgO particulate in the Example 4thermoset may have caused stress concentrations in the material duringtensile testing, thereby instigating smaller strains to failure.

As noted above, preparation of the composition of Example 4 onlydiffered from preparation of the composition of Example 3 in that theMgO was introduced before the distillation step for the composition ofExample 3 but the MgO was introduced after the distillation step for thecomposition of Example 4. FIG. 3 through FIG. 5, however, illustratethat this preparation change had a measurable effect on the resultingphysical properties of the compositions. Introducing the MgO before thedistillation step provided a much flatter zero-shear viscosity profile,slightly lower crystallization temperatures for the resin and thethermoset, and a significantly greater toughness of the resultingcomposition relative to introducing the MgO after the distillation step.

Finally, as shown in FIG. 6, Fourier-transform infrared (FTIR) analysisof the thermoset samples revealed an absorbance peak at about 1590 cm⁻¹for both the Example 3 MgO-doped PGS thermoset FTIR spectrum and theExample 4 MgO-doped thermoset FTIR spectrum that is not present in thecontrol PGS thermoset FTIR spectrum. Without wishing to be bound bytheory, this absorption peak may be due to either coordination of theMg′ species by the negatively-charged carboxylic acids of PGS or byesterification of the PGS to the hydroxylated surface of the Mg(OH)₂particles.

While the invention has been described with reference to one or moreexemplary embodiments, it will be understood by those skilled in the artthat various changes may be made, and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims. In addition, all numerical values identified in the detaileddescription shall be interpreted as though the precise and approximatevalues are both expressly identified.

What is claimed is:
 1. A method of treating a bone defect, the methodcomprising: molding a bone filling composite and placing the bonefilling composite in the bone defect; wherein the bone filling compositecomprises a bone filler comprising microparticles of at least oneelastomeric material, a carrier material comprising a poly(glycerolsebacate) resin, and a biologic medium.
 2. The method of claim 1,wherein the biologic medium is selected from the group consisting ofblood, serum, demineralized bone matrix, bone chips, bone morphogenicproteins, and combinations thereof.
 3. The method of claim 1, whereinthe carrier material further comprises a material selected from thegroup consisting of a polypeptide, a polysaccharide, aglycosaminoglycan, a hydrogel, and combinations thereof.
 4. The methodof claim 1, wherein the microparticles comprise thermoset poly(glycerolsebacate).
 5. The method of claim 1, wherein the molding comprisesmixing the bone filler, the carrier material, and the biologic medium toform the bone filling composite.
 6. The method of claim 5, wherein themolding occurs before the placing.
 7. The method of claim 1, wherein themolding comprises forming a sheet of the bone filling composite.
 8. Abone filling composite comprising: a bone filler comprisingmicroparticles of at least one elastomeric material; a carrier materialcomprising a poly(glycerol sebacate) resin; and a biologic medium. 9.The bone filling composite of claim 8, wherein the biologic medium isselected from the group consisting of blood, serum, demineralized bonematrix, bone chips, bone morphogenic proteins, and combinations thereof.10. The bone filling composite of claim 8, wherein the carrier materialfurther comprises a material selected from the group consisting of apolypeptide, a polysaccharide, a glycosaminoglycan, a hydrogel, andcombinations thereof.
 11. The bone filling composite of claim 8, whereinthe microparticles comprise thermoset poly(glycerol sebacate).